p75 Neurotropin Receptor(p75NTR) is a transmembranous Neurotrophin/proNeurotrophin receptor with low binding affinity and no intracellular domain kinase activity(Chao et al. 1995). The primary described functional role of p75NTR appears to be attributable to its Trk Receptor-interacting properties. Additional functions of P75NTR proteins continue to be investigated, as the protein appears to be a novel player in multiple neuronal processes including both Sortilin-proNGF mediated and independent apoptosis of cells(Barker. 2004). Overall, the role of p75NTR in regulating cell survival, both neuronal and otherwise, is not fully understood. However, p75NTR is gradually revealing itself to be a significant and diverse player in the development of an understanding of NGF and neurotrophin-mediated cell signaling and survival systems.
The presence p75NTR has been histochemically identified in many tissue types with specific patterns of expression during the embryonic development of rats(Wheeler et al. 1998). p75NTR expression occurs both simultaneously and independently of Trk's. Expression lessens and becomes more restricted to neuronal and some non-neuronal tissue sub-types during maturation. It is hence inferred that p75NTRs are particularly relevant in the selective death of redundant cells during embryonic development(Wheeler et al. 1998)(Nykjaer et al. 2005).
p75NTR is a 75kD(399 amino-acid) transmembrane receptor of the Tumor Necrosis Factor Receptor superfamily("Death receptors"). p75NTR shares functional roles with both Trk and TNFR's but is structurally distinct from both(Schor et al. 2005). The extracelluar domain is possessed of quaduplicate cysteine-rich neurotrophin/pro-NT binding regions(Lad et al. 2003). p75NTR binds ligands uniquely when compared to other TNFR's in that it binds ligands in soluble dimeric form and is capable of participating in numerous coreceptor complexes - whereas TNFRs typically act independently via ligation with homotrimeric type II transmembrane signaling proteins(Barker. 2004). Similarly, the ~80 amino acid intracellular "death domain" commonly present in TNFR's as a mechanism to interact with caspase8-adaptor proteins is structurally different from that of other TNFRs and initiates signaling cascades by an alternative pathway combination(Chao et al. 1995). The extracellular and juxta-membrane "stalk" regions are N- and O-glycoslated respectively due to an artifact from the cleavage of a 28 amino-acid signaling peptide during membrane insertion(Schor et al. 2005).
Cytoplasmic "Tail" Domain Cleavage:p75NTR can exist in a cleaved residue form proceeding the cleavage of the intracellular domain(ICD) by alpha-secretase and TNF-alpha convertase(Nykjaer et al. 2005). The function of this activity is unknown but the subsequent residue retains its Trk-interacting capacity whilst reducing the apoptotic capacity of the receptor in question. However, in some circumstances the overall susceptibility of the cell to apoptosis signaling is increased by this activity, possibly due to the poorly described mechanism of cleaved ectodomain translocation into the nucleus - where it appears to act as a transcription factor for NF-kappaB(Nykjaer et al. 2005).
s-p75NTR: A variant of p75NTR exists wherein the neurotrophin binding domain(EC) is lost during post-transcriptional splicing of exonIII of the p75NTR locus. The absence of the exodomains in knockout mice indicates the preservation of proapoptotic potential in s-p75NTR's and the autonomic signaling mechanisms of soluble ICDs(Nykjaer et al. 2005).
Function and Known Dynamics
The function of p75NTRs, as with many other NT-mediated signaling processes, appears less distinct the more we examine its intricacies. Particularly, p75NTR appears to play a far more dynamic role in cell survival functions than is possible with a binary-style signaling mechanism.
Attenuation of Trks: 75NTRs are implicated as being key to non-saturative NT responses 'in vitro' via attenuation of the Trk signaling pathway- and thus induction of cell survival mechanisms. There are multiple proposed mechanisms for the increased responsiveness of Trk's to Neurotropins at below-saturative levels:
- p75NTR may be involved the presentation of ligand to Trk's - This proposed mechanism has lost favor recently due to a lack of corresponding data and the greater strength of other theories. However it is notable that, due to the high binding affinity of p75NTR for TRK ligands, p75NTR may be involved in clearing ligand bound to Trk receptors and thus contribute to the observed reduction of unbiquitination of p75NTR co-expressed Trk's(Chao et al. 1995)
- Contribute to formation of High-affinity binding site: significant evidence has compiled to indicate that, when co-expressed with Trk's, p75NTR enhances Trk ligand binding and response and increases the discrimination of Trk family members for their preferred ligands. In this model, p75NTR acts appears to act as a coreceptor for neurotrophin in the formation of a p75NTR-dimerTrk complex(Barker. 2004) (Lad et al. 2003). This complex is has a much greater binding affinity for NT's due to the formation of a high-affinity Trk binding site in addition the formation of multiple new and pre-existing low-affinity binding regions upon the complexed molecules(Barker. 2004) (Lad et al. 2003). The proposed mechanism for this change in receptor affinity implicates conformational changes during binding of constituent co-receptors(Lad et al. 2003)
Initiation of Apoptosis:Paradoxically, the independent and non-Trk coreceptor (ie: w/Sortilin) action of p75NTR is characterised as being pro-apoptotic in response to the same family of ligands as Trk's in addition to their pro-forms(more efficaciously)or even in the absence of ligation(Nykjaer et al. 2005).
Cell Survival and Inhibition of Apoptosis: In alternative systems, P75NTR has been observed mediating cell survival and inhibiting pro-apoptotic pathways when bound with NGF(Schor et al. 2005)(Nykjaer et al. 2005). The mechanisms by which p75NTR can differentially induce antagonistic pathways via complexing with the same ligand is not fully understood. However, it has been postulated that in such an instance, NGF binding inhibits the pro-apoptotic properties of unbound p75NTR(Nykjaer et al. 2005). Although this does not fully explain the observed behaviors of p75NTR it is concordant with similar paradoxical observations in other TNF receptors and thus unlikely to be an error of observation. This property of p75NTR is thought to be exhibited variably between different tissue subtypes(Nykjaer et al. 2005)
Furthermore, association with Nogo-R and LINGO-1 in the presence of myelin-based growth inhibitors (MBGI)has been observed to activate Rho complex-mediated regenerative effects during stressor events(Nykjaer et al. 2005)
Thus, it appears that p75NTRs are participating in a complex syncidium of neurotrophin-mediated signaling mechanisms whose function is to tightly regulate various factors affecting cell survival and differentiation in neuronal and some non-neuronal tissues. The precise nature of this system is yet to be categorically defined.
- Nina Felice Schor: The p75 neurotrophin receptor in human development and disease. Progress in Neurobiology 77 (2005) 201–214
- E.F. WHEELER, H. GONG, R. GRIMES, D. BENOIT, AND L. VAZQUEZ: p75NTR and Trk Receptors are Expressed in Reciprocal Patterns in a Wide Variety of Non-Neural Tissues During Rat Embryonic Development, Indicating Independent Receptor Functions.THE JOURNAL OF COMPARATIVE NEUROLOGY 391:407–428 (1998)
- Rabizadeh S, Rabizadeh S, Ye X, Wang JJ, Bredesen DE: Neurotrophin dependence mediated by p75NTR: contrast between rescue by BDNF and NGF. Cell Death and Differentiation (December 1999) Volume 6, Number 12, Pages 1222-1227
- Philip A. Barker: p75NTR Is Positively Promiscuous: Novel Partners and New Insights. Neuron, Vol. 42, 529–533, May 27, 2004
- Shivanand P. Lad , Daniel A. Peterson , Ralph A. Bradshaw and Kenneth E. Neet: Individual and Combined Effects of TrkA and p75NTR Nerve Growth Factor Receptors: A ROLE FOR THE HIGH AFFINITY RECEPTOR SITE. J. Biol. Chem., Vol. 278, Issue 27, 24808-24817, July 4, 2003
- MARIANO BARBACID: Structural and Functional Properties of the TRK Family of Neurotrophin Receptors. Volume 766 Issue Receptor Activation by Antigens Cytokines Hormones and Growth Factors, Pages 442 - 458 (1995)
- Mariano Barbacid: The Trk family of neurotrophin receptors. Journal of Neurobiology. Vol 25, No. I I , pp. 1386-1403 (1994)
- Moses V. Chao and Barbara L. Hempstead: p75 and Trk: A two-receptor system. Volume 18, Issue 7, July 1995, Pages 321-326
- Anders Nykjaer, Thomas E Willnow and Claus Munck Petersen: p75NTR – live or let die. Current Opinion in Neurobiology Volume 15, Issue 1, February 2005, Pages 49-57
*Image 1: constructed from information from ref: Schlor, 2005
**Image 2: constructed from information and reference figures (where indicated) from: (Nykjaer et al. 2005- Figures 1,2 & 3),(Lad et al, 2002), (Rabizadeh et al. 1999. Figure 4), (Barker. 2004. Figures 1 & 3), (Chao, Homestead. 1995. Figure 3) (Barbicid, 1995. Figure 1)
6CD - 6 cysteine Domain
DD - Death Domain
EC - Extracellular
ECD - Extracellular domain
IC - intracelluar
ICD - Intracelluar Domain
MBGI - Myelin Based Growth Inhibitor
NF-kappa-B - Nerve Factor Kappa B.
NGF - Nerve Growth Factor
NT - Neurotrophin
TNFR - Tumor Necrosis Factor Receptors
--Peter Kehoe 21:44, 20 May 2009 (EST)